[Diagnostic significance of immunologic study of cerebrospinal fluid in neuroinfections].
An increase in the antibody titre in the blood serum, previously considered sufficient for determining the etiology of neuroinfection can no longer be regarded as a satisfactory index in the light of the contemporary level of our knowledge. The literature and the authors' own data show the importance of a simultaneous examination of antibodies in the cerebrospinal fluid and the blood serum in some neuroinfections. For example, the determination in the cerebrospinal fluid of antibodies to herpes simplex virus in herpetic encephalitis is considered sufficient (in the presence of the characteristic clinical picture) to make the diagnosis of this severe disease. The examination of antibodies to herpes simplex virus in the cerebrospinal fluid of 35 patients with a suspected herpetic encephalitis revealed their presence in 34% of those studied. The data obtained suggest that immunoassay of the cerebrospinal fluid and blood sera should be used on a broader scale in patients with acute and chronic neuroinfections. The method plays an the early diagnosis of these diseases and early administration of the appropriate treatment.


Translational remodeling by RNA-binding proteins and noncoding RNAs.
Responsible for generating the proteome that controls phenotype, translation is the ultimate convergence point for myriad upstream signals that influence gene expression. System-wide adaptive translational reprogramming has recently emerged as a pillar of cellular adaptation. As classic regulators of mRNA stability and translation efficiency, foundational studies established the concept of collaboration and competition between RNA-binding proteins (RBPs) and noncoding RNAs (ncRNAs) on individual mRNAs. Fresh conceptual innovations now highlight stress-activated, evolutionarily conserved RBP networks and ncRNAs that increase the translation efficiency of populations of transcripts encoding proteins that participate in a common cellular process. The discovery of post-transcriptional functions for long noncoding RNAs (lncRNAs) was particularly intriguing given their cell-type-specificity and historical definition as nuclear-functioning epigenetic regulators. The convergence of RBPs, lncRNAs, and microRNAs on functionally related mRNAs to enable adaptive protein synthesis is a newer biological paradigm that highlights their role as "translatome (protein output) remodelers" and reinvigorates the paradigm of "RNA operons." Together, these concepts modernize our understanding of cellular stress adaptation and strategies for therapeutic development. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications Translation > Translation Regulation Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs.


A Nutrigenomic Approach to Non-Alcoholic Fatty Liver Disease.
Following the epidemics of obesity due to the consumption of high-calorie diet and sedentary lifestyle, nonalcoholic fatty liver disease (NAFLD) is now the leading cause of liver disease in Western countries. NAFLD is epidemiologically associated with metabolic syndrome and insulin resistance, and in susceptible individuals it may progress to cirrhosis and hepatocellular carcinoma. Genetic factors play a key role in NAFLD predisposition by interacting with nutritional and other environmental factors. To date, there is no drug therapy for the treatment of NAFLD, and the main clinical recommendation is lifestyle modification. In the last years, nutrigenomics is promoting an increased understanding of how nutrition affects the switch from health to disease by altering the expression of an individual's genetic makeup. The present review tries to summarize the most recent data evidencing how the interactions between nutrients and genetic factors can influence NAFLD development. The final goal should be to develop tools to quantify these complex interactions. The definition of a "nutrigenomic risk score" for each individual may represent a novel therapeutic approach for the management of NAFLD patients.


The impact of phenocopy on the genetic analysis of complex traits.
A consistent debate is ongoing on genome-wide association studies (GWAs). A key point is the capability to identify low-penetrance variations across the human genome. Among the phenomena reducing the power of these analyses, phenocopy level (PE) hampers very seriously the investigation of complex diseases, as well known in neurological disorders, cancer, and likely of primary importance in human ageing. PE seems to be the norm, rather than the exception, especially when considering the role of epigenetics and environmental factors towards phenotype. Despite some attempts, no recognized solution has been proposed, particularly to estimate the effects of phenocopies on the study planning or its analysis design. We present a simulation, where we attempt to define more precisely how phenocopy impacts on different analytical methods under different scenarios. With our approach the critical role of phenocopy emerges, and the more the PE level increases the more the initial difficulty in detecting gene-gene interactions is amplified. In particular, our results show that strong main effects are not hampered by the presence of an increasing amount of phenocopy in the study sample, despite progressively reducing the significance of the association, if the study is sufficiently powered. On the opposite, when purely epistatic effects are simulated, the capability of identifying the association depends on several parameters, such as the strength of the interaction between the polymorphic variants, the penetrance of the polymorphism and the alleles (minor or major) which produce the combined effect and their frequency in the population. We conclude that the neglect of the possible presence of phenocopies in complex traits heavily affects the analysis of their genetic data.


TNF-alpha antagonism in severe asthma?
A small minority of patients with asthma have severe disease that is refractory or poorly responsive and remain persistently symptomatic despite maximal inhaled therapy. These patients represent an important unmet clinical need as they suffer considerable morbidity and mortality and consume a disproportionately large amount of health care resource. Tumour necrosis factor- alpha (TNF-α) is a pro-inflammatory cytokine that has been implicated in many aspects of the airway pathology in asthma. Evidence is emerging to suggest that it may play an important role in severe, refractory disease. The development of novel TNF-α antagonist has allowed us to test the role of this cytokine in vivo. Early studies demonstrated an improvement in asthma quality-of-life, lung function, airway hyperresponsiveness (AHR) and a reduction in exacerbation frequency, in patients treated with anti-TNF-α therapy. However, there is marked heterogeneity in response suggesting that benefit is likely to be reserved to a small sub-group. This view is supported by the lack of efficacy in later large clinical trials, although subgroups of responders were identified. Importantly, concerns have been raised about the safety of anti-TNF-α therapies in severe asthma. Therefore, current evidence suggests that the risk of anti- TNF-α therapies outweighs benefit in severe asthma. In this review, we will discuss the role of TNF-α biology and its role in severe asthma, the clinical trials conducted so far and summarize the patents related to TNF-α and the antagonist drug therapies.


Imaging of the Lamina Cribrosa using Swept-Source Optical Coherence Tomography.
The lamina cribrosa (LC) is the presumed site of axonal injury in glaucoma. Its deformation has been suggested to contribute to optic neuropathy by impeding axoplasmic flow within the optic nerve fibers, leading to apoptosis of retinal ganglion cells. To visualize the LC in vivo, optical coherence tomography (OCT) has been applied. Spectral domain (SD)-OCT, used in conjunction with recently introduced enhanced depth imaging (EDI)-OCT, has improved visualization of deeper ocular layers, but in many individuals it is still limited by inadequate resolution, poor image contrast and insufficient depth penetrance. The posterior laminar surface especially is not viewed clearly using these methods. New generation high-penetration (HP)-OCTs, also known as swept-source (SS)-OCT, are capable to evaluate the choroid in vivo to a remarkable level of detail. SS-OCTs use a longer wavelength (1,050 nm instead of 840 nm) compared to the conventional techniques. We review current knowledge of the LC, findings from trials that use SD-OCT and EDI-OCT, and our experience with a prototype SS-OCT to visualize the LC in its entirety. Key Points What is known? • The LC is the presumed site of axonal injury in glaucoma • Compared to spectral domain-OCT, enhanced depth imaging-OCT improves imaging of the LC • Even so, currently used SD-OCT techniques are restricted by poor wavelength penetrance of the deeper ocular layers What our findings add? • SS-OCT may be a superior imaging modality for deep ocular structures • Prior studies used SS-OCT to evaluate choroidal thickness in both healthy and 'normal tension glaucoma' eyes • SS-OCT enables good evaluation of three-dimension (3D) lamina cribrosa morphology. How to cite this article: Nuyen B, Mansouri K, Weinreb RN. Imaging of the Lamina Cribrosa using Swept-Source Optical Coherence Tomography. J Current Glau Prac 2012;6(3): 113-119.


Using a standing-tree acoustic tool to identify forest stands for the production of mechanically-graded lumber.
This study investigates how the use of a Hitman ST300 acoustic sensor can help identify the best forest stands to be used as supply sources for the production of Machine Stress-Rated (MSR) lumber. Using two piezoelectric sensors, the ST300 measures the velocity of a mechanical wave induced in a standing tree. Measurements were made on 333 black spruce (Picea mariana (Mill.) BSP) trees from the North Shore region, Quebec (Canada) selected across a range of locations and along a chronosequence of elapsed time since the last fire (TSF). Logs were cut from a subsample of 39 trees, and sawn into 77 pieces of 38 mm × 89 mm cross-section before undergoing mechanical testing according to ASTM standard D-4761. A linear regression model was developed to predict the static modulus of elasticity of lumber using tree acoustic velocity and stem diameter at 1.3 m above ground level (R2 = 0.41). Results suggest that, at a regional level, 92% of the black spruce trees meet the requirements of MSR grade 1650Fb-1.5E, whilst 64% and 34% meet the 2100Fb-1.8E and 2400Fb-2.0E, respectively. Mature stands with a TSF < 150 years had 11 and 18% more boards in the latter two categories, respectively, and therefore represented the best supply source for MSR lumber.


Development and validation of the Minnesota borderline personality disorder scale.
Although large epidemiological data sets can inform research on the etiology and development of borderline personality disorder (BPD), they rarely include BPD measures. In some cases, however, proxy measures can be constructed using instruments already in these data sets. In this study, the authors developed and validated a self-report measure of BPD from the Multidimensional Personality Questionnaire (MPQ). Items for the new instrument-the Minnesota BPD scale (MBPD) -were identified and refined using three large samples: undergraduates, community adolescent twins, and urban substance users. The authors determined the construct validity of the MBPD scale by examining its association with (a) diagnosed BPD, (b) questionnaire-reported BPD symptoms, and (c) clinical variables associated with BPD: suicidality, trauma, disinhibition, internalizing distress, and substance use. The authors also tested the MBPD scale in two prison inmate samples. Across samples, the MBPD scores correlated with BPD indices and external criteria and showed incremental validity above measures of negative affect, thus supporting its construct validity as a measure of BPD.


Histopathologic features of canine heartworm microfilarial infection after treatment with ivermectin.
Tissues of dogs treated with ivermectin were examined microscopically to learn the fate of microfilariae of canine heartworm that disappear from the peripheral circulation within a few days of treatment. Medicated dogs were killed 18 hours, 3 days, and 6 days after treatment with 0.5 mg of ivermectin/kg of body weight subcutaneously. Ivermectin was dissolved in 60% propylene glycol and 40% glycerol formal. In dogs killed at posttreatment hour 18, the peripheral microfilaremia had decreased by an average of 89%. At this time, a dense mass of RBC, WBC, and macrophages plus many microfilariae was found in pulmonary alveolar septae. Similar reactions were seen in liver, kidney, and spleen. Phagocytosis of microfilarial fragments was evident. In dogs killed at posttreatment day 3, many microfilariae were fragmented and phagocytosis of the fragments was common. In dogs killed at posttreatment day 6, microgranulomas were common, particularly in such vascular organs as lungs, kidney, and liver. Microgranulomas containing microfilariae were also seen in spleen, skeletal and cardiac muscles, diaphragm, lymph nodes, gastrointestinal tract, and pancreas. Small glial nodules were seen in the CNS. Denudation of the atrial epicardium was associated with fragments of microfilariae and granulomatous inflammatory cells. Renal epithelial crescents were observed in treated and nontreated dogs. Plasma cells were conspicuous in treated and nontreated dogs, especially in some livers and kidneys. Before treatment, all dogs were severely microfilaremic. At the end of the experiment, the peripheral microfilaremia was reduced by 98%.(ABSTRACT TRUNCATED AT 250 WORDS)


Induction of melanin synthesis in albino mouse skin by DNA from pigmented mice.
Skin cells from albino mouse embryos have been shown to synthesize melanin after exposure to a nucleoprotein fraction of cells from pigmented mice. Although transformed clones were not found in any of 37 control experiments, at least 15 transformations took place in 10 of a series of 49 experiments using undegraded DNA. The active component in the transforming material appears to be DNA because DNase-treated preparations did not induce melanin synthesis.


Isolation and initial structure-functional characterization of endogenous tRNA-derived stress-induced RNAs.
Recent transcriptome-wide studies have identified a diverse pool of transfer RNA (tRNA)-derived RNAs or tRNA-derived fragments (tRFs). Some of these RNAs have been demonstrated to be functional and involved in multiple biological processes ranging from the regulation of gene expression to transgenerational epigenetic inheritance. Post-transcriptional maturation of tRNAs includes various processing events including extensive decoration by various RNA modifications, which are required for correct tRNA folding and stability. Moreover, tRNA modifications determine the pattern and specificity of tRNA cleavage. The major drawbacks of many studies in the field of tRFs are that most of them used synthetic RNAs that closely mimic endogenous tRFs in their sequence, yet lack RNA modification that is found in vivo. Here, we developed a simple method to isolate tRNA-derived stress-induced RNAs (tiRNAs), a specific subset of tRFs. Our approach is scalable, cost-effective and relies on the purification of individual tiRNAs based on a sequence-specific RNA/DNA isolation technique using DNA probes. Our method facilitates functional studies of tiRNAs by addressing how physiological RNA modifications within tRNA fragments affect their biological activities. Here, we report pilot functional studies on selected endogenous tiRNAs, namely tiRNAAla and tiRNAGly. We show that natural 5'-tiRNAAla molecules assemble into G-quadruplex structures, and endogenous 5'-tiRNAGly possesses translation inhibition activity.


Visual biofeedback balance training using wii fit after stroke: a randomized controlled trial.
[Purpose] The aim of the present study was to investigate the effect of balance training with visual biofeedback on balance, body symmetry, and function among individuals with hemiplegia following a stroke. [Subjects and Methods] The present study was performed using a randomized controlled clinical trial with a blinded evaluator. The subjects were twenty adults with hemiplegia following a stroke. The experimental group performed balance training with visual biofeedback using Wii Fit(®) together with conventional physical therapy. The control group underwent conventional physical therapy alone. The intervention lasted five weeks, with two sessions per week. Body symmetry (baropodometry), static balance (stabilometry), functional balance (Berg Balance Scale), functional mobility (Timed Up and Go test), and independence in activities of daily living (Functional Independence Measure) were assessed before and after the intervention. [Results] No statistically significant differences were found between the experimental and control groups. In the intragroup analysis, both groups demonstrated a significant improvement in all variables studied. [Conclusion] The physical therapy program combined with balance training involving visual biofeedback (Wii Fit(®)) led to an improvement in body symmetry, balance, and function among stroke victims. However, the improvement was similar to that achieved with conventional physical therapy alone.


Optimization the soda-AQ process for cellulose pulp production and energy content of black liquor from L. leucocephala K360.
A commercial variety of Leucaena leucocephala K360 was used for pulp production and papermaking employing the soda-anthraquinone process. Also, the chemical and energy contents of the resultant black liquors were determined to simultaneously optimize: pulp and paper production and energy generation. A process temperature of (185°C), an operating time of (120 min) and an active alkali concentration of (21%) provided sheets of paper with good strength (tensile index of 12.12 Nm/g, burst index of 0.38 kPa m(2)/g, tear index of 1.29 mN m(2)/g and a Kappa number of 20.5) and black liquor with a greater calorific value (14.1 MJ/kg) than that obtained with higher active alkali concentrations. However, reducing the active alkali concentration to a level in the low operation range led to less marked degradation of cellulose and allowed paper sheets with good properties to be obtained and energy to be optimally produced from the black liquor.


Leptin regulates MMP-2, TIMP-1 and collagen synthesis via p38 MAPK in HL-1 murine cardiomyocytes.
A clear association between obesity and heart failure exists and a significant role for leptin, the product of the obese gene, has been suggested. One aspect of myocardial remodeling which characterizes heart failure is a disruption in the balance of extracellular matrix synthesis and degradation. Here we investigated the effects of leptin on matrix metalloproteinase (MMP) activity, tissue inhibitor of metalloproteinase (TIMP) expression, as well as collagen synthesis in HL-1 cardiac muscle cells. Gelatin zymographic analysis of MMP activity in conditioned media showed that leptin enhanced MMP-2 activity in a dose- and time-dependent manner. Leptin is known to stimulate phosphorylation of p38 MAPK in cardiac cells and utilization of the p38 MAPK inhibitor, SB203580, demonstrated that this kinase also plays a role in regulating several extracellular matrix components, such that inhibition of p38 MAPK signaling prevented the leptin-induced increase in MMP-2 activation. We also observed that leptin enhanced collagen synthesis determined by both proline incorporation and picrosirius red staining of conditioned media. Pro-collagen type-I and pro-collagen type-III expression, measured by real-time PCR and Western blotting were also increased by leptin, effects which were again attenuated by SB203580. In summary, these results demonstrate the potential for leptin to play a role in mediating myocardial ECM remodeling and that the p38 MAPK pathway plays an important role in mediating these effects.


Dipole states and coherent interaction in surface-acoustic-wave coupled phononic resonators.
Manipulation of mechanical motion at the micro-scale has been attracting continuous attention, leading to the successful implementation of various strategies with potential impact on classical and quantum information processing. We propose an approach based on the interplay between a pair of localised mechanical resonators and travelling surface acoustic waves (SAW). We demonstrate the existence of a two-sided interaction, allowing the use of SAW to trigger and control the resonator oscillation, and to manipulate the elastic energy distribution on the substrate through resonator coupling. Observation of the vectorial structure of the resonator motion reveals the existence of two coupling regimes, a dipole-dipole-like interaction at small separation distance versus a surface-mediated mechanical coupling at larger separation. These results illustrate the potential of this platform for coherent control of mechanical vibration at a resonator level, and reciprocally for manipulating SAW propagation using sub-wavelength elements.


Dynactin is required to maintain nuclear position within postmitotic Drosophila photoreceptor neurons.
How a nucleus is positioned within a highly polarized postmitotic animal cell is not well understood. In this work, we demonstrate that the Dynactin complex (a regulator of the microtubule motor protein Dynein) is required to maintain the position of the nucleus within post-mitotic Drosophila melanogaster photoreceptor neurons. We show that multiple independent disruptions of Dynactin function cause a relocation of the photoreceptor nucleus toward the brain, and that inhibiting Dynactin causes the photoreceptor to acquire a bipolar appearance with long leading and trailing processes. We find that while the minus-end directed motor Dynein cooperates with Dynactin in positioning the photoreceptor nucleus, the plus-end directed microtubule motor Kinesin acts antagonistically to Dynactin. These data suggest that the maintenance of photoreceptor nuclear position depends on a balance of plus-end and minus-end directed microtubule motor function.


Family history of malignant or benign thyroid tumors: implications for surgical procedure management and disease-free survival.
Current guidelines lack a standardized management for patients with family history of thyroid carcinoma (fTC),particularly benign thyroid neoplasm (fBTN). Our objective was to investigate the influence of various family histories on the selection of surgical approaches and disease-free survival (DFS). A cohort study was conducted involving 2261 patients diagnosed with differentiated thyroid carcinoma including those with fTC (n=224), fBTN (n=122), and individuals without a family history of thyroid carcinoma (nfTC; n=1915). Clinicopathological characteristics were collected. DFS was estimated using Kaplan-Meier analysis and factors affecting DFS were identified using Cox proportional hazard model. Compared to nfTC, small tumor size, clinically lymph node-positive, extrathyroidal extension, vascular invasion, Hashimoto's disease and nodular goiter were more common in fTC and fBTN groups. They had lower T stage and a lower rate of good response to TSH suppression therapy but received more radioiodine therapy. It is worth noting that fTC is associated with male, bilateral and multifocal tumors, as well as central lymph node metastasis and distant metastasis. Both fTC (aHR = 2.45, 95% CI=1.11-5.38; P = 0.03) and fBTN (aHR = 3.43, 95% CI=1.27-9.29; P = 0.02) were independent predictors of DFS in patients who underwent lobectomy, but not total thyroidectomy. For 1-4 cm thyroid carcinomas with clinically node-negative, fTC was identified as an independent predictor, whereas fBTN was not. Our findings indicate that a family history, particularly of malignancy, is associated with a more aggressive disease. Family history does not affect the prognosis of patients who undergo total thyroidectomy, but it may increase the risk of postoperative malignant events in those who have a lobectomy. Additionally, it may be necessary to monitor individuals with a family history of benign thyroid neoplasms.


Preventing cisplatin induced ototoxicity by N-acetylcysteine and salicylate.
In this study we investigated if CP induced ototoxicity could be prevented or reduced by the use of salicylate and N-acetylcysteine. Fifty-four patients (28 females, 26 males; mean age 37+/-9.5 years; range 29 to 71 years) who had cisplatin chemotherapy due to solid organ tumors were enrolled in the study. The patients were randomized into three groups, with 18 patients in each group. The first group (control group) received cisplatin, second group received N-acetylcysteine (NAC; 600 mg/day) with cisplatin and the third group received salicylate (300 mg/day) with cisplatin. All patients evaluated audiologically including high frequency audiometry and auditory brainstem response. The cisplatin-induced ototoxic damage could be reduced in 10,000 and 12,000 Hz frequencies when N-acetylcysteine was added to the cisplatin therapy protocol. There was no decrease in the hearing loss levels of the patients who were receiving cisplatin with salicylate. According to auditory brainstem response testing results, there was no difference detected between N-acetylcysteine or salicylate for the amelioration of cisplatin induced ototoxicity.


[Effect of impulse infrared laser radiation on bioenergetic metabolism in gastric mucosa in patients with gastroduodenal ulcer].
Gastric mucosa and blood plasm were studied in 82 patients with gastroduodenal ulcer for content of adenylic nucleotides (AMP, ADP and ATP), histamine, amino acids. It was found that the above nucleotides occurred in the examinees in subnormal quantities. The necessary substrates, aspartate in particular, were deficient. This may lead to impairment of biosynthetic processes, to imbalance of defense factors. Photon therapy of gastroduodenal ulcer corrects bioenergetic metabolism in gastric mucosa thus producing a marked therapeutic effect.


The novel Listeria monocytogenes bile sensor BrtA controls expression of the cholic acid efflux pump MdrT.
Mammalian bile has potent anti-microbial activity, yet bacterial pathogens of the gastrointestinal tract and hepatobiliary system nonetheless persist and replicate within bile-rich environments. Listeria monocytogenes, a Gram-positive pathogen, encounters bile at three stages throughout its infectious cycle in vivo: in the gut during initial infection, in the liver where it replicates robustly and in the gallbladder, from which it can return to the intestine and thence to the environment. The mechanisms by which L. monocytogenes senses mammalian bile and counteracts its bactericidal effects are not fully understood. In this report, we have determined the L. monocytogenes bile-induced transcriptome, finding that many critical virulence factors are regulated by bile. Among these, the multidrug efflux pumps MdrM and MdrT, previously shown to be critical for the bacterial provocation of a pathogenesis-promoting host innate immune response, are robustly and specifically induced by the bile component cholic acid. This induction is mediated by BrtA, the first identified L. monocytogenes sensor of bile, which loses the ability to bind to and repress the mdrT promoter in the presence of cholic acid. We show that MdrT can export cholic acid, and that ΔmdrT bacteria are significantly attenuated both in vitro when exposed to cholic acid or bile, and in vivo in the gallbladders and livers of infected mice.


Estrogen and progesterone exposure is reduced in response to energy deficiency in women aged 25-40 years.
Alterations in circulating steroids are believed to be important mediators of the impact that diet and exercise have on breast cancer risk and changes in bone density. This study aimed to test the hypothesis that moderate exercise training combined with caloric restriction would produce significant menstrual disturbances and alterations in ovarian steroids in premenopausal women. Sedentary premenopausal women (25-40 years; body mass index: 23.6 +/- 0.6 kg/m(2)) assigned to either a light conditioning (LC, n = 9) or an exercise combined with caloric restriction group (EX + CR, n = 24) were studied for one screening, one baseline and four intervention periods equivalent to the length of subjects' menstrual cycles. Exercise consisted of supervised training sessions, i.e. two LC or four EX + CR times per week, 30-60 min at a moderate intensity. The EX + CR group was prescribed a diet representing a caloric restriction of 20-35% below baseline energy requirements, whereas the LC group remained eucaloric. Ovarian steroid exposure was determined with daily urinary estrone-1- and pregnanediol glucuronides (E1G and PdG, respectively) and mid-cycle urinary LH measures. Fitness, body composition, and serum sex hormone binding globulin (SHBG) and serum estradiol (E2) were assessed repeatedly. The intervention produced significant increases in VO(2) max and decreases in both body weight (-3.7 +/- 0.5 kg; ranged from -8.8 to +1.8 kg) and percent body fat (-4.5 +/- 0.7%; ranged from -12 to +0.3%), which were attributable primarily to changes in the EX + CR subjects (time x group; P < 0.05). Serum E2 and urinary E1G and PdG concentrations declined significantly across the intervention period (time; P < 0.05), whereas SHBG increased transiently (time; P < 0.05) in the EX + CR subjects, with no significant changes observed in the LC group. The decrease in E1G area under the curve was significantly related to the daily energy deficit (R =0.61; P = 0.003), not the amount of weight lost. There was no significant impact of the intervention on menstrual cyclicity or the incidence of menstrual disturbances in either group. A moderate aerobic exercise training program combined with modest weight loss in accordance with recommended guidelines produces significant reductions in ovarian steroid exposure without disrupting menstrual cyclicity in premenopausal women aged 25-40 years. Exposure to a daily energy deficit is a stronger predictor of the decline in estrogen exposure than decreases in body weight.


Noninvasive assessment of tumor VEGF receptors in response to treatment with pazopanib: a molecular imaging study.
Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) drive angiogenesis, and several VEGFR inhibitors are already approved for use as single agents or in combination with chemotherapy. Although there is a clear benefit with these drugs in a variety of tumors, the clinical response varies markedly among individuals. Therefore, there is a need for an efficient method to identify patients who are likely to respond to antiangiogenic therapy and to monitor its effects over time. We have recently developed a molecular imaging tracer for imaging VEGFRs known as scVEGF/(99m)Tc; an engineered single-chain (sc) form of VEGF radiolabeled with technetium Tc 99m ((99m)Tc). After intravenous injection, scVEGF/(99m)Tc preferentially binds to and is internalized by VEGFRs expressed within tumor vasculature, providing information on prevalence of functionally active receptors. We now report that VEGFR imaging readily detects the effects of pazopanib, a small-molecule tyrosine kinase inhibitor under clinical development, which selectively targets VEGFR, PDGFR, and c-Kit in mice with HT29 tumor xenografts. Immunohistochemical analysis confirmed that the changes in VEGFR imaging reflect a dramatic pazopanib-induced decrease in the number of VEGFR-2(+)/CD31(+) endothelial cells (ECs) within the tumor vasculature followed by a relative increase in the number of ECs at the tumor edges. We suggest that VEGFR imaging can be used for the identification of patients that are responding to VEGFR-targeted therapies and for guidance in rational design, dosing, and schedules for combination regimens of antiangiogenic treatment.


Morphine enhances tissue content of collagen and increases wound tensile strength.
Morphine is a commonly prescribed analgesic for wound pain. Previous studies have shown that morphine enhances accumulation of collagen in cultured fibroblasts. Because fibroblasts are important for the remodeling of connective tissue in incisional wound, this study investigates the biological effects of morphine on cutaneous collagen content and wound tensile strength. A full-thickness incisional wound (2 cm in length) was created on the dorsum of mice followed by treatment with placebo or morphine (5 and 20 mg/kg/day, i.p.). Fourteen days later, tensile strength of the healed incisional wound was measured using a tensiometer. Protein expression of transforming growth factor (TGF)-beta1 and matrix metalloproteinases (MMP)-2 in the incisional wound tissue was analyzed. Degree of tissue remodeling and levels of collagen were determined by histological examination and a dye-binding collagen assay, respectively. Morphine enhanced the breaking strength of incisional wound 14 days after treatment (92 +/- 10, 102 +/- 10 and 134 +/- 12 mg for control, morphine 5 mg/kg/day and morphine 20 mg/kg/day, respectively; P = 0.03, n = 6-7). Protein expression of TGF-beta1 and MMP-2 was significantly enhanced in mice treated with morphine. Histological examination of the wound tissue showed evidence of increased thickness of the cutaneous fibrous layer and deposition of collagen in the high-dose morphine treatment group. Collagen assays also demonstrated that tissue concentrations of collagen were significantly increased in the wound tissue of morphine-treated animals on day 2 of drug treatment. The present study demonstrates that systemic administration of morphine enhances tissue collagen deposition in the cutaneous tissue, thereby increasing the tensile strength of the incisional wound.


Design strategy for a near-infrared fluorescence probe for matrix metalloproteinase utilizing highly cell permeable boron dipyrromethene.
Near-infrared (NIR) fluorescence probes are especially useful for simple and noninvasive in vivo imaging inside the body because of low autofluorescence and high tissue transparency in the NIR region compared with other wavelength regions. However, existing NIR fluorescence probes for matrix metalloproteinases (MMPs), which are tumor, atherosclerosis, and inflammation markers, have various disadvantages, especially as regards sensitivity. Here, we report a novel design strategy to obtain a NIR fluorescence probe that is rapidly internalized by free diffusion and well retained intracellularly after activation by extracellular MMPs. We designed and synthesized four candidate probes, each consisting of a cell permeable or nonpermeable NIR fluorescent dye as a Förster resonance energy transfer (FRET) donor linked to the NIR dark quencher BHQ-3 as a FRET acceptor via a MMP substrate peptide. We applied these probes for detection of the MMP activity of cultured HT-1080 cells, which express MMP2 and MT1-MMP, by fluorescence microscopy. Among them, the probe incorporating BODIPY650/665, BODIPY-MMP, clearly visualized the MMP activity as an increment of fluorescence inside the cells. We then applied this probe to a mouse xenograft tumor model prepared with HT-1080 cells. Following intratumoral injection of the probe, MMP activity could be visualized for much longer with BODIPY-MMP than with the probe containing SulfoCy5, which is cell impermeable and consequently readily washed out of the tissue. This simple design strategy should be applicable to develop a range of sensitive, rapidly responsive NIR fluorescence probes not only for MMP activity, but also for other proteases.


Do high participation rates improve effects of population-based general health checks?
The aim is to investigate if the effect of a health check differs between areas with different participation rates. The Inter99 population-based randomized lifestyle intervention study covered 73 areas within the suburbs of Copenhagen, Denmark. Adults aged 30-60years were randomly drawn from a population and were randomized to intervention group (n=11,483) or control group (n=47,122). Participation rates in the health check varied considerably between areas (mean 52%; range 35-85%). In separate survival analyses, area participation rate was included both as a continuous exposure variable and as a categorical variable (tertiles; low: 35-49%, meddle: 50-54%, high: 55-84%). All persons in the intervention and control group were followed in registers for 10-year total mortality and combined events (ischemic heart disease, stroke, or both). In adjusted models (including sociodemographic variables, ethnicity, number of children and comorbidity), among men, there was no difference in risk of death between areas with varying participation rates. Surprisingly, among women living in high-participation areas a significantly higher risk of all-cause mortality (HR: 1.32 [1.03-1.69]) was found in the intervention group (ref=controls). For both men and women, in no areas there was any difference between intervention and control group in incident IHD/stroke. Higher participation rates in population based health checks is probably unlikely to improve the effects of these, and may in worst case be harmful in subgroups of the population. Further well-designed studies within non-participation research should have high priority and are required to establish link between health checks and risk of death in subgroups of the population.


Peri-operative risk factors for delayed gastric emptying after a pancreaticoduodenectomy.
Delayed gastric emptying (DGE) is a frequent cause of morbidity, prolonged hospital stay and readmission after a pancreaticoduodenectomy (PD). We sought to evaluate predictive peri-operative factors for DGE after a PD. Four hundred and sixteen consecutive patients who underwent a PD at our tertiary referral centre were identified. Univariate and multivariate (MV) logistic regression models were used to assess peri-operative factors associated with the development of clinically significant DGE and a post-operative pancreatic fistula (POPF). DGE occurred in 24% of patients (n = 98) with Grades B and C occurring at 13.5% (n = 55) and 10.5% (n = 43), respectively. Using MV regression, a body mass index (BMI) ≥35 [odds ratio (OR) = 3.19], operating room (OR) length >5.5 h (OR = 2.72) and prophylactic octreotide use (OR = 2.04) were independently associated with an increased risk of DGE. DGE patients had a significantly longer median hospital stay (12 versus 7 days), higher 90-day readmission rates (32% versus 18%) and an increased incidence of a pancreatic fistula (59% versus 27%). When controlling for POPF, only OR length >5.5 h (OR 2.73) remained significantly associated with DGE. DGE remains a significant cause of morbidity, increased hospital stay and readmission after PD. Our findings suggest patients with a BMI ≥35 or longer OR times have a higher risk of DGE either independently or through the development of POPF. These patients should be considered for possible enteral feeding tube placement along with limited octreotide use to decrease the potential risk and consequences of DGE.


Examining compliance with ethical standards for animal research: is there a need for refinement? A qualitative study from northern Europe.
Ethical guidelines for research on animals such as the 3Rs (Replacing, Reducing, Refining) and positive harm-benefit evaluations are anchored in EU Directive 2010/63. In this qualitative study we investigated how ethical guidelines interact and/or compete with other considerations when animal research is planned. Four focus groups consisting mainly of researchers involved in animal use were conducted in four Northern European countries and findings were analysed thematically with the support of NVIVO. Practical issues and the importance of doing good science were dominant topics. Practical issues could not easily be separated from the goal of good science. Participants expressed concerns which accord with the core-values of the 3Rs, but in one group they explicitly referred to the 3Rs as a concept. Conflicts between reductions in animal numbers and the risk of creating unreliable results were addressed. They also criticized the practice of using more animals to improve statistical figures to get results published in highly ranked journals - a finding we believe is new. The main conclusion of this study is that ethical values could not easily be separated from the goal of producing good science. Whereas policy makers seem to expect researchers to explicitly take ethical considerations into account, we found that their ethical thinking is mainly manifested as an implicit part of methodology and design. We don't see this as a problem as long as the underlying core values are implicitly respected, or promoted, in the relevant experimental practice.


Anatomy and lessons of partnerships in global pediatric surgery.
Partnerships in Global Surgery have evolved over several decades and continue to do so based on reports from different experiences and collaborations. These should be characterised by their objectives, leadership and "championship," communication, ethics and equity. Partnerships take the form of academic collaborations or clinical support whose details vary with the different stakeholders involved. Over time, these have evolved based on challenges, successes, and failures. Recently, quality improvement activities have been increasingly initiated with locally derived information. This has come from local databases in low and middle income country (LMIC) settings whose maintenance and analysis have been done through academic collaborations. For many sites in LMICs, there would be very little advance in paediatric surgery without collaborations. Despite this, problems still arise from collaborations due to failure to learn from past problems, lack of local championship, poor communication, and externally driven objectives. For success and longevity, the collaboration must pay attention to unique the needs of the site, champions and equity.


Image Segmentation for High-Density Surface Electromyography Mappings of Pelvic Floor Muscle Activity of Women with Interstitial Cystitis/Bladder Pain Syndrome.
Interstitial cystitis/bladder pain syndrome (IC/BPS) can result in pelvic floor muscle (PFM) overactivity. Current clinical assessment protocols include basic electromyographic assessment of PFM activation; however, they do not provide a comprehensive assessment localized to each region of the PFM. We examined the ability of high-definition features from intravaginal high-density surface electromyography (HD-sEMG) to assess the severity of PFM overactivity in female IC/BPS patients. HD-sEMG was collected from fifteen female IC/BPS patients and fifteen urologically healthy female controls. The 2D mappings of root mean squared amplitude (RMS) at rest normalized by maximal voluntary contraction (resting RMS ratios) were segmented via k-means to identify areas of peak activity and surrounding activity. Female IC/BPS patients exhibited significantly greater resting RMS ratios for peak activity (p=0.0096), surrounding activity (p=0.0003), and average activity (p=0.0016) compared to healthy female controls. Furthermore, the area of peak activity was significantly larger for female IC/BPS patients than for healthy female controls (p=0.0063). Image segmentation of intravaginal HD-sEMG provides a more robust biomarker of PFM as compared to current methods.


Latent human herpesvirus 6 is reactivated in CAR T cells.
Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6)1. Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4+ T cells. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (about 1 in 300-10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration2 or are in clinical studies3-5, we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials1,6-8 and may influence the design and production of autologous and allogeneic cell therapies.


A validated method for analysis of Swerchirin in Swertia longifolia Boiss. by high performance liquid chromatography.
Swertia spp. (Gentianaceae) grow widely in the eastern and southern Asian countries and are used as traditional medicine for gastrointestinal disorders. Swerchirin, one of the xanthones in Swertia spp., has many pharmacological properties, such as, antimalarial, antihepatotoxic, and hypoglycemic effects. Because of the pharmacological importance of Swerchirin in this investigation, it was purified from Swertia longifolia Boiss. as one of the main components and quantified by means of a validated high performance liquid chromatography (HPLC) technique. Aerial parts of the plant were extracted with acetone 80%. Phenolic and non-phenolic constituents of the extract were separated from each other during several processes. The phenolic fraction was injected into the semi-preparative HPLC system, which consisted of a C(18) column and a gradient methanol: 0.1% formic acid mode. Using this method, we were able to purify six xanthones from the plant, in order to use them as standard materials. The analytical method was validated for Swerchirin as one of the most important components of the plant, with more pharmacological activities according to the validation parameters, such as, selectivity, linearity (r(2) > 0.9998), precision (</=3.3), and accuracy, which were measured by the determination of recovery (98-107%). The limits of detection and quantization were found to be 2.1 and 6.3 mug/mL, respectively. On account of the speed and accuracy, the UV-HPLC method may be used for quantitative analysis of Swerchirin.


Proanthocyanidin in red rice inhibits MDA-MB-231 breast cancer cell invasion via the expression control of invasive proteins.
Proanthocyanidin is one of the main active compounds found in red jasmine rice. We previously reported that red rice extract could reduce cancer cell invasion. However, the direct effect of proanthocyanidin from red rice on the invasion of cancer cells and the exact molecular mechanism remained unclear. Here, we report for the first time that proanthocyanidin-rich fraction from red rice (PRFR) reduced the migration and invasion of MDA-MB-231 human breast cancer cells. The types of proanthocyanidin in PRFR were identified as procyanidins and prodelphinidins by acid hydrolysis. For cancer cell invasion, degradation of the extracellular matrix (ECM) is required. Treatment of the cells with PRFR reduced the expression of ECM degradation-associated proteins, including matrix metalloproteinase-9 (MMP-9), membrane type-1 matrix metalloproteinase, urokinase plasminogen activator, urokinase plasminogen activator receptor and plasminogen activator-1. Moreover, PRFR also reduced the activity of collagenase and MMP-9. Furthermore, PRFR significantly suppressed the expression of intercellular adhesion molecule-1 and interleukin-6. We also found that PRFR reduced the DNA-binding activity of nuclear factor kappa B (NF-κB), which is the expressed mediator of ECM degradation-associated proteins. These results suggest that proanthocyanidin from red rice mediates MDA-MB-231 breast cancer cell invasion by altering the expression of the invasion-associated proteins, possibly by targeting NF-κB activity.


No evidence of increased risk for schizophrenia or bipolar affective disorder in persons with aneuploidies of the sex chromosomes.
Several case reports and reviews have suggested an increased incidence of schizophrenia or bipolar disorder among persons with sex chromosome aneuploidies, but this observation may have been caused by biased sampling. The 1122 individuals with sex chromosome aneuploidies registered in the Danish Cytogenetic Central Register were screened in the Danish Psychiatric Central Register for admissions with schizophrenia or bipolar affective disorder. Both registers are population based and have existed since 1968 and 1969 respectively. Relative risks were calculated for schizophrenia, bipolar affective disorder and either schizophrenia or bipolar disorder combined as one phenotype. Since hospitalization for a psychiatric disorder increases the probability that a cytogenetic examination is performed, the relative risks could be inflated, and they were therefore adjusted accordingly. Aneuploidies of the X or Y chromosomes were not associated with an increased risk of schizophrenia or bipolar disorder. The occurrence of the combined phenotype including both schizophrenia and bipolar disorder was significantly reduced among persons with Turner's syndrome and significantly increased among individuals with the 47, XYY karyotype. This population-based study did not find evidence supporting the presence of risk alleles for schizophrenia or bipolar disorder on the X chromosome or the pseudoautosomal region on the Y chromosome. The findings of an increased risk for the combined phenotype to XYY males and the reduced risk for persons with Turner's syndrome are interesting but difficult to explain with present neurobiological knowledge and inconsistent with the other findings of the study.


Leveraging water, sanitation and hygiene for nutrition in low- and middle-income countries: A conceptual framework.
In low- and middle-income countries (LMICs), access to water, sanitation and hygiene (WASH) is associated with nutritional status including stunting, which affects 144 million children under 5 globally. Despite the consistent epidemiological association between WASH indicators and nutritional status, the provision of WASH interventions alone has not been found to improve child growth in recent randomized control trials. We conducted a literature review to develop a new conceptual framework that highlights what is known about the WASH to nutrition pathways, the limitations of certain interventions and how future WASH could be leveraged to benefit nutritional status in populations. This new conceptual framework will provide policy makers, program implementors and researchers with a visual tool to bring into perspective multiple levels of WASH and how it may effectively influence nutrition while identifying existing gaps in implementation and research.


Fokker-Planck analysis of separation dependent potentials and diffusion coefficients in simulated microscopy experiments.
Total internal reflection microscopy (TIRM) and video microscopy (VM) are methods for nonintrusively measuring weak colloidal interactions important to many existing and emerging applications. Existing analyses of TIRM measured single particle trajectories can be used to extract particle-surface potentials and average particle diffusion coefficients. Here we develop a Fokker-Planck (FP) formalism to simultaneously extract both particle-surface interaction potentials and position dependent diffusion coefficients. The FP analysis offers several advantages including capabilities to measure separation dependent hydrodynamic interactions and nonequilibrium states that are not possible with existing analyses. The FP analysis is implemented to analyze Brownian dynamic simulations of single particle TIRM and VM experiments in several configurations. Relative effects of spatial and temporal sampling on the correct interpretation of both conservative and dissipative forces are explored and show a broad range of applicability for accessible experimental systems. Our results demonstrate the ability to extract both static and dynamic information from microscopy measurements of isolated particles near surfaces, which provides a foundation for further investigation of particle ensembles and nonequilibrium systems.


State-to-state variations in newborn screening policies.
Population-based newborn screening for genetic and metabolic disorders is standard practice in all states in the United States. Policies governing newborn screening are determined at the state level; however, and thus, a great degree of variability exists between states regarding many facets of such screening. To gather information relating to the processes, content, and outcomes of policy making affecting newborn screening programs across the United States. We surveyed the directors of newborn screening programs for each of the 50 states using a postal questionnaire. The questionnaire solicited information about the specific tests incorporated in each state's panel of screening tests and information pertaining to the policy-making processes by which decisions are reached regarding this testing. Substantial variation exists across states regarding both the processes of policy formulation and the outcomes of decisions made about newborn screening. All states currently screen for phenylketonuria and congenital hypothyroidism. Extensive variation exists across states in testing for other disorders. The processes by which state policy makers arrive at decisions in this area are extremely diverse. Almost three fourths of the states have standing expert advisory bodies who issue recommendations regarding screening program modifications, but the authority granted to these panels varies substantially. Some regional cooperation in this area exists. Further development of regional cooperation could offer some states greater efficiency in both laboratory testing and screening policy formulation. From the standpoint of an individual state. Wisconsin's approach to policy development in this area is described as a model worthy of consideration.


Comparison of the yield and miss rate of narrow band imaging and white light endoscopy in patients undergoing screening or surveillance colonoscopy: a meta-analysis.
Colonoscopy has an appreciable miss rate for adenomas and colorectal cancer. The goal of advanced endoscopic imaging is to improve lesion detection. Compared with standard definition, high-definition (HD) colonoscopes have the advantage of increased field of visualization and higher resolution; narrow band imaging (NBI) utilizes narrow band filters for enhanced visualization of surface architecture and capillary pattern. The objective of this study was to compare the yield and miss rates of HD-NBI and HD-WLE (white light endoscopy) for the detection of colon polyps using meta-analysis. A recursive literature search of randomized controlled trials (RCTs) comparing the yield of HD-NBI and HD-WLE for detection of colon polyps in patients undergoing screening/surveillance colonoscopy. Authors were contacted for missing data. In RCT with tandem colonoscopy (RCT-t), findings from the first-pass examinations were used in the yield analysis and from the tandem pass for the miss rate analysis. Data on the yield of polyps were extracted, pooled, and analyzed using RevMan 4.2.9 software. Odds ratio (OR) and 95% confidence intervals (CIs) for the pooled data for the yield and miss rates of NBI and WLE were calculated. A fixed effect model (FEM) was used for analyses without, and a random effect model (REM) for analyses with heterogeneity. The yield analysis revealed no significant difference between HD-NBI and HD-WLE for the detection of adenomas (six studies; n=2,284; OR: 1.01; CI: 0.74-1.37; REM); patients with polyps (six studies; n=2,275; OR: 1.15; CI: 0.8-1.64; REM); patients with adenomas (four studies; n=2,177; OR: 1.0; CI: 0.83-1.20; FEM); detection of adenomas <10 mm (five studies; n=1,618; OR: 1.32; CI: 0.92-1.88; FEM); flat adenomas (five studies; n=1,675; OR: 1.26; CI: 0.62-2.57; REM); and flat adenomas per patient (five studies; n=2,200; OR: 1.63; CI: 0.71-3.74; REM). The miss rate analysis revealed no difference in polyp miss rate (three studies; n=524; OR: 1.17; CI: 0.8-1.71; FEM) or adenoma miss rate (three studies; n=524; OR: 0.65; CI: 0.4-1.06; FEM) between the two techniques. Compared with HD-WLE, HD-NBI does not increase the yield of colon polyps, adenomas, or flat adenomas, nor does it decrease the miss rate of colon polyps or adenomas in patients undergoing screening/surveillance colonoscopy.


"Lipase Only, Please": Reducing Unnecessary Amylase Testing.
Serum amylase testing is not recommended for the workup of acute pancreatitis; yet it is commonly ordered in acute care settings. This was a student-led quality improvement initiative with application of a pre-post study design at two urban hospitals: Mount Sinai Hospital, a 1,134-bed academic hospital, and Mount Sinai Queens, a 235-bed community hospital. The multifaceted intervention combined a targeted educational and awareness campaign with the decoupling of amylase from electronic order sets (at the academic hospital only), as well as a nonintrusive electronic medical record (EMR) advisory statement (at both hospitals). Monthly amylase orders were tracked for all emergency department visits and hospital admissions between January 2016 and May 2018 for both hospitals RESULTS: There was a significant and sustained decrease in amylase ordering at both the academic hospital (from 3,214 orders per month to 2,348 orders per month; p = 0.011) and the community hospital (from 100 orders per month to 23 orders per month; p = 0.001). Specifically, the nonintrusive EMR order advisory statement was independently associated with a significant reduction in serum amylase ordering. There was an estimated net annual cost reduction of $44,999. This student-led initiative was successful in reducing unnecessary amylase ordering across two diverse institutions through a combination of education, publicity, and EMR changes.


The Evolution of the Charge Transport Mechanism in Single-Molecule Break Junctions Revealed by Flicker Noise Analysis.
The electronic noise characterization of single-molecule devices provides insights into the mechanisms of charge transport. In this work, it is reported that flicker noise can serve as an indicator of the time-dependent evolution of charge transport mechanisms in the single-molecule break junction process. By introducing time-frequency analysis, the authors find that flicker noise components of the molecule junction show time evolution behavior in the dynamic break junction process. A further investigation of the power-law dependence of flicker with conductance during the dynamic break junction process reveals that the mechanism of charge transport transits from the through-space transport to the through-bond transport, and is dominated by through-space transport again when the junction is about to rupture. The authors' results provide a flicker noise-based way to characterize the time-dependent evolution of charge transport mechanisms in single-molecule break junctions.


Functionality and transduction condition evaluation of recombinant Klf4 for improved reprogramming of iPS cells.
The induced pluripotent stem cell (iPSC) technology holds great potential in regenerative therapy. iPSCs could be induced by proteins (piPSC) linked with poly-arginine cell-penetrating peptides (CPPs) without the risk of genomic alteration, athough with extremely low efficiency and delayed reprogramming. We aimed to evaluate the reprogramming potency of purified mouse Klf4 proteins linked with the CPP of HIV transactivator of transcription (TAT) or Drosophila Penetratin protein at the N- or C-terminus. Eukaryotically expressed recombinant Klf4 targeted cell nucleus while the purified proteins localized in the cytoplasmic and peri-nuclear region. However, using a combined transduction of Klf4 protein and retroviruses expressing Oct4, Sox2, and c-Myc (OSM), we found both TAT- and penetratin-linked Klf4 proteins significantly induced mouse iPSC formation at the nanomolar level in 2 to 4 weeks. Klf4 protein with TAT at the N-terminus showed no reprogramming activity while the fusion protein, with Discosoma red fluorescent protein (DsRed) between TAT and Klf4, exhibited significant iPSC induction function. The iPSCs induced by Klf4 protein and retroviral OSM combinations were pluripotent. Using the protein/retroviral OSM reprogramming assay, we further evaluated Klf4 protein transduction conditions and showed that four continued transductions by purified Klf4 proteins are sufficient for effective iPSC induction. Our results demonstrated for the first time that TAT- and Penetratin-linked Klf4 proteins can effectively replace viral Klf4 in reprogramming fibroblasts, and provided a valuable strategy to evaluate recombinant proteins and transduction conditions for the improvement of piPSC induction efficiency.


Health and social precursors of unemployment in young men in Great Britain.
To identify health and socioeconomic factors in childhood that are precursors of unemployment in early adult life and to examine the hypothesis that young men who become unemployed are more likely to have accumulated risks to health during childhood. Longitudinal birth cohort study. The amount of unemployment experienced in early adult life up to age 32 years was the outcome measure used. Exposure measures to indicate vulnerability to future ill health were: height at age 7 years and the Bristol social adjustment guide (BSAG) at age 11 years, a measure of behavioural maladjustment. Socioeconomic measures were: social class at birth, crowding at age 7, qualifications attained before labour market entry, and region of residence. Great Britain. Altogether 2256 men with complete data from the national child development study (NCDS). The NCDS has collected data on all men and women born in one week in 1958 and has followed them up using interviews, self completion questionnaires, and medical examinations at birth and at ages 7, 11, 16, 23 and 33 years. A total of 269 men (11.9%) experienced more than one year of unemployment between ages 22 and 32 years. Poor socioeconomic conditions in childhood and a lack of qualifications were associated with an increased risk of unemployment. Geographical region was also significant in determining the risk of unemployment. Men with short stature and poor social adjustment in childhood were more likely to experience unemployment in adult life, even after controlling for socioeconomic background, education, and parental height. These differences remained when those with chronic childhood illnesses were excluded from the analysis. The adjusted relative odds for experiencing more than one year of unemployment between ages 22 and 32 years for men who were in the top fifth of the BSAG distribution (most maladjusted) compared with those in the bottom fifth were 2.36 (95% CI 1.49, 3.73). The adjusted relative odds for experiencing more than one year of unemployment between ages 22 and 32 years for men who were in the bottom fifth of the distribution of height at age 7 years (indicating slowest growth) compared with those in the top fifth, were 2.41 (95% CI 1.43, 4.04). Adult height was not significantly associated with unemployment. The relationship between unemployment and poor health arises, in part, because men who become unemployed are more likely to have accumulated risks to health during childhood, reflected by slower growth and a greater tendency to behavioural maladjustment. Short stature in childhood is a significant indicator of poor socioeconomic circumstances in childhood and reflects earlier poor development.


Fatty acids affect micellar properties and modulate vitamin D uptake and basolateral efflux in Caco-2 cells.
We have recently shown that vitamin D3 (cholecalciferol) absorption is not a simple passive diffusion but involves cholesterol transporters. As free fatty acids (FAs) modulate cholesterol intestinal absorption and metabolism, we hypothesized that FAs may also interact with vitamin D absorption. Effects of FAs were evaluated at different levels of cholecalciferol intestinal absorption. First, the physicochemical properties of micelles formed with different FAs were analyzed. The micelles were then administered to human Caco-2 cells in culture to evaluate FA effects on (i) cholecalciferol uptake and basolateral efflux and (ii) the regulation of genes coding proteins involved in lipid absorption process. Micellar electric charge was correlated with both FA chain length and degree of unsaturation. Long-chain FAs at 500 μM in mixed micelles decreased cholecalciferol uptake in Caco-2 cells. This decrease was annihilated as soon as the long-chain FAs were mixed with other FAs. Oleic acid significantly improved cholecalciferol basolateral efflux compared to other FAs. These results were partly explained by a modulation of genes coding for lipid transport proteins such as Niemann-pick C1-like 1 and scavenger receptor class B type I. The data reported here show for the first time that FAs can interact with cholecalciferol intestinal absorption at different key steps of the absorption process. Cholecalciferol intestinal absorption may thus be optimized according to oil FA composition.


Improved titer and stability of selenium nanoparticles produced by engineered Saccharomyces cerevisiae.
Selenium nanoparticles (SeNPs) have gained significant attention in the fields of medicine and healthcare products due to their various biological activities and low toxicity. In this study, we focused on genetically modifying the Saccharomyces cerevisiae strain YW16 (CICC 1406), which has the ability to efficiently reduce sodium selenite and produce red SeNPs. By overexpressing genes involved in glutathione production, we successfully increased the glutathione titer of the modified strain YJ003 from 41.0 mg/L to 212.0 mg/L. Moreover, we improved the conversion rate of 2.0 g/L sodium selenite from 49.3% to 59.6%. Furthermore, we identified three surface proteins of SeNPs, and found that overexpression of Act1, one of the identified proteins, led to increased stability of SeNPs across different acid-base and temperature conditions. Through a 135-h feed fermentation process using 5.0 g/L sodium selenite, we achieved an impressive conversion rate of 88.7% for sodium selenite, and each gram of SeNPs contained 195.7 mg of selenium. Overall, our findings present an efficient method for yeast to synthesize SeNPs with high stability. These SeNPs hold great potential for applications in nanomedicine or as nutritional supplements to address selenium deficiency.


Heaving buoys, point absorbers and arrays.
Absorption of wave energy may be considered as a phenomenon of interference between incident and radiated waves generated by an oscillating object; a wave-energy converter (WEC) that displaces water. If a WEC is very small in comparison with one wavelength, it is classified as a point absorber (PA); otherwise, as a 'quasi-point absorber'. The latter may be a dipole-mode radiator, for instance an immersed body oscillating in the surge mode or pitch mode, while a PA is so small that it should preferably be a source-mode radiator, for instance a heaving semi-submerged buoy. The power take-off capacity, the WEC's maximum swept volume and preferably also its full physical volume should be reasonably matched to the wave climate. To discuss this matter, two different upper bounds for absorbed power are applied in a 'Budal diagram'. It appears that, for a single WEC unit, a power capacity of only about 0.3 MW matches well to a typical offshore wave climate, and the full physical volume has, unfortunately, to be significantly larger than the swept volume, unless phase control is used. An example of a phase-controlled PA is presented. For a sizeable wave-power plant, an array consisting of hundreds, or even thousands, of mass-produced WEC units is required.


Summary: multiple primary cancers in Denmark, 1943-80.
The risk of developing a second primary cancer was studied among 171,749 men and 208,192 women who were reported to the Danish Cancer Registry between 1943 and 1980. Only those who survived at least 2 months were included in the analysis, and more than 1.7 million person-years of observation were accrued. Altogether, 15,084 second primary cancers developed in organs other than the initial cancer site [relative risk (RR) = 0.99]. Adjustment for possible underreporting of multiple primary cancers increased the RR to 1.06. The overall RR of a second cancer developing for all sites was 0.91, but interpretation of this risk is difficult because new tumors arising within the same organ are generally not recorded in Denmark. The RR for all sites increased with time from 0.94 during the first decade of follow-up (excluding the first year) to 1.13 among 30-year survivors. Patients below the age of 20 years when first diagnosed with cancer experienced significantly increased risk of developing a second cancer. Elevated risks were also observed for sites thought to have a common etiology. For example, cancers of smoking-related sites were increased in both directions for cancers of the oral cavity, respiratory tract, and urinary organs. For cancers suspected to have a hormone- or dietary fat-related association, significant reciprocal relationships were seen among cancers of the endometrium, ovary, and colon. Cancer treatment probably is an important factor in second cancer development, even when judged indirectly in the present study. For example, radiotherapy may have been responsible for an elevated risk of subsequent cancers of the thyroid, breast, colon, rectum, bladder, connective tissue, and hematopoietic system in long-term survivors. Chemotherapy may have increased the risk of subsequent leukemias. Our data further indicate that cancer patients have no general susceptibility to develop new malignant tumors, although high rates may be found for particular sites sharing common risk factors. Conversely, the occurrence of one cancer does not appear to protect against developing a new cancer.


An improved theory of the electric conductance of ionic solutions based on the concept of the ion-atmosphere's smaller-ion shell.
Although the electric conductivity of ionic solutions is of great importance in science and technology, complete understanding of the physical factors and principles underlying ion and charge transport in solution has so far been missing. The Debye-Hückel-Onsager (DHO) theory of the equivalent ionic conductivity (λi for single ion i, Λ for a binary electrolyte) is a limiting law of only a few electrolyte valence families, and its extension to solution of finite concentration has not been entirely successful; at most, it has led to semiempirical expressions of λi or Λ vs. concentration (c), incorporating adjustable parameters of no clear physical meaning. Improving the description of the ion atmosphere and including in the conductivity model the smaller-ion shell (SiS) of this atmosphere (D. Fraenkel, Mol. Phys., 2010, 108, 1435) allow now an extension of the DHO theory to a "DHO-SiS" theory that offers analytic expressions for λi and Λ as a function of c without adjustable parameters. The fit with experiment is very good, often excellent, for many electrolytes of the various valence families. λi values can be converted to single-ion activity coefficients, γis, suggesting that the latter ionic factors do have physical validity, contrary to what many literature sources claim. Together with the recently proposed theory of the limiting conductivities, λ0i and Λ0 (D. Fraenkel, Mol. Phys., 2018, 116, 2271), the new theory offers a simple and comprehensive ion conductivity treatment that improves upon existing theoretical treatments, with λi and Λ expressed by ionic sizes instead of λ0i and Λ0.


Calcium-rich diet and vitamin D supplementation improves lipid profiles and reduces atherogenic index in high salt fed male Wistar rat.
To ascertain the effect of calcium rich diet and/ or vitamin D supplementation on atherogenic parameters in high salt loaded rats. Thirty male rats were randomly assigned into five groups of six rats each, namely; control; salt only; salt + Calcium; salt + Vit. D and salt + Vit. D + Calcium. High salt diet constituted 8% NaCl diet + 1% NaCl drinking water, while calcium diet was made from 2.5% CaCl2 diet. Serum lipids and atherogenic indices were estimated using standard laboratory procedures. The control rats took normal rodent chow, the feeding lasted 6 weeks. Rats fed high salt diet only had significantly (p<0.05) reduced high density lipoprotein cholesterol levels, however this was significantly (p<0.05) increased upon treatment with calcium rich diet and vitamin D supplementation. The high salt groups placed on Vit. D and/or calcium diet supplementation had a significant (p<0.05) decrease in low density lipoproteins, total cholesterol and atherogenic indices (cardiac risk ratio, atherogenic coefficient and atherogenic index of plasma) compared to the group fed on high salt only. These results suggest the ameliorative potentials of calcium rich diets and vitamin D supplementation against atherogenic tendencies and possibly cardiovascular diseases.


CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer.
Background: Molecular targeting remains to be a promising approach in oncology. Overexpression of G protein-coupled receptors (GPCRs) in human cancer is offering a powerful opportunity for tumor-selective imaging and treatment employing nuclear medicine. We utilized novel chemerin-based peptide conjugates for chemokine-like receptor 1 (CMKLR1) targeting in a breast cancer xenograft model. Methods: By conjugation with the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), we obtained a family of five highly specific, high-affinity tracers for hybrid positron emission tomography/magnetic resonance (PET/MR) imaging. A xenograft model with target-positive DU4475 and negative A549 tumors in immunodeficient nude mice enabled CMKLR1-specific imaging in vivo. We acquired small animal PET/MR images, assessed biodistribution by ex vivo measurements and investigated the tracer specificity by blocking experiments. Results: Five CMKLR1-targeting peptide tracers demonstrated high biological activity and affinity in vitro with EC50 and IC50 values below 2 nM. Our target-positive (DU4475) and target-negative (A549) xenograft model could be validated by ex vivo analysis of CMKLR1 expression and binding. After preliminary PET imaging, the three most promising tracers [68Ga]Ga-DOTA-AHX-CG34, [68Ga]Ga-DOTA-KCap-CG34 and [68Ga]Ga-DOTA-ADX-CG34 with best tumor uptake were further analyzed. Hybrid PET/MR imaging along with concomitant biodistribution studies revealed distinct CMKLR1-specific uptake (5.1% IA/g, 3.3% IA/g and 6.2% IA/g 1 h post-injection) of our targeted tracers in DU4475 tumor tissue. In addition, tumor uptake was blocked by excess of unlabeled peptide (6.4-fold, 5.5-fold and 3.4-fold 1 h post-injection), further confirming CMKLR1 specificity. Out of five tracers, we identified these three tracers with moderate, balanced hydrophilicity to be the most potent in receptor-mediated tumor targeting. Conclusion: We demonstrated the applicability of 68Ga-labeled peptide tracers by visualizing CMKLR1-positive breast cancer xenografts in PET/MR imaging, paving the way for developing them into theranostics for tumor treatment.


[Adults with intellectual disability, a neglected group in health care].
Adults with intellectual developmental disorder are at considerable risk of somatic as well as psychiatric illness, but seldom have access to services on equal conditions as adults without intellectual developmental disorder. The symptoms of illness are often difficult to interpret, due to communication difficulties, and examinations may be difficult to carry out. Patients with moderate/severe/profound intellectual disability therefore need interpreters and to be given sufficient time when making clinic visits. Patients with intellectual disability have excess mortality from somatic illness and are at risk for suboptimal treatment with psychotropic medications.


Assessment of metal status in drainage canal water and their bioaccumulation in Oreochromis niloticus fish in relation to human health.
The purpose of this study was to assess metal concentrations (Al, Cd, Pb, Hg and Ni) in Sabal drainage canal (Al-Menoufiya Province, River Nile Delta, Egypt) water as well as their accumulation in some selected organs (skin, muscles and kidneys) of Oreochromis niloticus fish to evaluate their hazard levels in relation to the maximum residual limits for human consumption. Drainage canal water was found to be heavily polluted with metals which far exceeded the permissible limits. It was found that metals accumulated in organs of O. niloticus in concentrations higher than those of canal water. Kidneys of O. niloticus contained the highest concentrations of the detected metals, while skin appeared to be the least preferred site for the bioaccumulation of metals as the lowest metals concentrations were detected in this tissue. The present study shows that fish organs contained high levels of metals exceeding the permissible limits values. Metals in muscle of fish were higher than the maximum permissible concentrations for human consumption. Thus, consuming fish caught from drainage canals is harmful to the consumers.


Tacrolimus and Diabetes in Kidney Transplantation: The Impact of Cyp3a5 Gene Polymorphism.
To explore the correlation between single nucleotide polymorphisms (SNPs) of CYP3A4 rs2740574 and CYP3A5 rs776746 and post-transplant diabetes mellitus (PTDM) in Chinese renal allograft recipients treated with tacrolimus. A total of 244 patients treated with tacrolimus were included in this study, wherein DNA sequencing was detected through fluorescence in situ hybridization, and SNP genotyping was performed. Among the 244 patients, 44 (18%) developed PTDM. The PTDM group exhibited higher preoperative body mass index and fasting plasma glucose levels, with higher creatinine values one year after surgery. The CYP3A4 rs2740574 genotype was found to be unique in its homozygous AA form. For CYP3A5 rs776746, the genotypes were distributed as follows: 28 (11.5%) cases with AA, 101 (41.4%) cases with AG, and 115 (47.1%) cases with GG, respectively (P = .042). The AA genotype showed a statistically significant difference from both AG and GG genotypes. Furthermore, the A allele of CYP3A5 rs776746 was found to be associated with an increased risk for PTDM development. The occurrence of tacrolimus-related PTDM is associated with body mass index, fasting plasma glucose levels, and CYP3A5 genotype before renal transplantation. Post-transplant diabetes mellitus is correlated with unfavorable long-term renal graft function, whereas the expression of the CYP3A5 rs776746 gene is linked to an elevated risk of PTDM.


Risk factors for mortality and clinical presentation of monkeypox.
To describe risk factors for mortality and clinical characteristics in patients with mpox infection at a reference hospital in Mexico. A prospective cohort study was conducted from September to December 2022 at Hospital de Infectología La Raza National Medical Center. Study participants were patients that met operational definition of confirmed case of mpox according to WHO criteria. Information was obtained through a case report form that included epidemiological, clinical, and biochemical information. The follow-up period was from initial evaluation for hospitalization until discharge due to clinical improvement or death. Written informed consent was obtained from all participants. Seventy-two patients were included in the analysis, 64 of 72 (88.9%) were people with HIV (PWH). Of the total of patients 71 of 72 (98.6%) were male, with a median age of 32 years old [95% confidence interval (CI), interquartile range (IQR) 27-37]. Coinfection with sexually transmitted infections was reported in 30 of 72 (41.7%). The overall mortality was five of 72 (6.9%). The incidence of mortality rate in PWH was 6.3%. Median days from onset of symptoms to death from any cause during hospitalization was 50 days (95% CI, IQR 38-62). Risk factors for mpox mortality in the bivariate analysis were CD4 + cells count ≤100 cells/μl at the time of assessment RR 20 (95% CI, IQR 6.6-60.2) ( P < 0.001), absence of antiretroviral therapy RR 6.6 (95% CI, IQR 3.6-12.1) ( P = 0.001) and ≥50 skin lesions at presentation RR 6.4 (95% CI, IQR 2.6-15.7) ( P = 0.011). The clinical presentation between PWH and non-HIV patients was similar in this study, however, reported mortality was associated with advanced-HIV disease.


Crash types: markers of increased risk of alcohol-involved crashes among teen drivers.
Teens drink/drive less often than adults but are more likely to crash when they do drink/drive. This study identified alcohol-related crash types for which teen drivers were at greater risk compared with adults. Michigan State Police crash records for drivers ages 16-19 (teens) and 45-65 years (adults) who experienced at least one crash from 1989 to 1996 were used to create alcohol crash types consisting of alcohol-related crashes that included specific combinations of other crash characteristics, such as drinking and driving at night (i.e., alcohol/nighttime). These data were combined with data from the 1990 and 1995 National Personal Travel Surveys and the 2001 National Household Travel Survey to estimate rates and rate ratios of alcohol-related crash types based on person-miles driven. Teens were relatively less likely than adults to be involved in alcohol-related crashes but were significantly more likely to be in alcohol-related crashes that included other crash characteristics. Teen males' crash risk was highest when drinking and driving with a passenger, at night, at night with a passenger, and at night on the weekend, and casualties were more likely to result from alcohol-related nighttime crashes. All the highest risk alcohol-related crash types for teen female drinking drivers involved casualties and were most likely to include speeding, passenger presence, and nighttime driving. The frequency with which passengers, nighttime or weekend driving, and speeding occurred in the highest risk alcohol-related crash types for teens suggests that these characteristics should be targeted by policies, programs, and enforcement to reduce teen alcohol-related crash rates.


Individual differences and the characterization of animal models of psychopathology: a strong challenge and a good opportunity.
Despite the development of valuable new techniques (i.e., genetics, neuroimage) for the study of the neurobiological substrate of psychiatric diseases, there are strong limitations in the information that can be gathered from human studies. It is thus critical to develop appropriate animal models of psychiatric diseases to characterize their putative biological bases and the development of new therapeutic strategies. The present review tries to offer a general perspective and several examples of how individual differences in animals can contribute to explain differential susceptibility to develop behavioral alterations, but also emphasizes methodological problems that can lead to inappropriate or over-simplistic interpretations. A critical analysis of the approaches currently used could contribute to obtain more reliable data and allow taking full advantage of new and sophisticated technologies. The discussion is mainly focused on anxiety-like and to a lower extent on depression-like behavior in rodents.


Two brothers with Martsolf's syndrome.
Two brothers affected by a syndrome consisting of short stature, hypogonadism, and severe mental retardation are reported. The syndrome shares the features of that described by Martsolf et al in two brothers born to a consanguineous Polish Jewish couple. Although our patients' parents are Sephardic Jews, they deny consanguinity. These observations and personal knowledge of another affected Jewish boy raise the question of whether Martsolf's syndrome is a new entity that should be included in the group of those that affect mainly Jewish people, and whether its pattern of inheritance is X linked recessive or autosomal recessive limited to males.


Effects of acidic amino acid antagonists upon the spectral properties of carp horizontal cells: circuitry of the outer retina.
The acidic amino acid receptor antagonists, alpha-methylglutamate and alpha-aminoadipate, were applied to the carp retina to study their effects upon the spectral properties of horizontal cells and to elucidate the synaptic connections between horizontal cells and cones. Application of these antagonists strongly hyperpolarized the L-type cone horizontal cells and reduced the responses of these horizontal cells to red light more than to blue light. Application of Co2+ ions to the retina, a procedure which decreases transmitter release, also hyperpolarized the L-type cone horizontal cells but reduced the response of these horizontal cells to red and blue lights equally. These results suggest that red- or long wavelength-sensitive cones release a different transmitter onto L-type cone horizontal cells than do short wavelength-sensitive cones. Application of the acidic amino acid antagonists also revealed details of the feedback pathway from L-type cone horizontal cells to cones. Previous studies have shown that feedback varies directly with stimulus size and that the effects of feedback on the responses of cones are observed as a transient waveform at response onset (a large, hyperpolarizing potential that is quickly followed by a smaller plateau potential). Application of the acidic amino acid antagonists at a dose which partially hyperpolarized the horizontal cells selectively enhanced the response of the cells to blue lights, when full field, and not spot, stimuli were used. The antagonists also eliminated the transient at response onset. These findings are consistent with the presence of a feedback pathway from L-type cone horizontal cells to short wavelength cones but not to long (red-sensitive) cones.


Effect of injected glucagon or fatty acids on mitochondrial ATPase.
The intraperitoneal injection of glucagon or the intravenous infusion of oleic acid provoked a rapid change in the properties of rat liver mitochondrial ATPase. When mitochondria of treated animals were isolated an increase in ATPase activity was observed as well as a modification on the response to activators and inhibitors and to the sulfhydryl reagent N-ethylmaleimide. Sensitivity to the activators dinitrophenol or bicarbonate decreased, whereas the sensitivity to inhibitors KOCN and KSCN increased, and an inhibitory effect of N-ethylmaleimide appeared. These effects gradually disappeared when mitochondrial suspensions were kept at 10 degrees C, and after approximately 5 h ATPase from mitochondria of treated and control animals behaved almost identically. If the oxidizing agent dichlorophenolindophenol was added to the isolated mitochondria the effects induced by glucagon or fatty acids immediately disappeared. The activation caused by the reducing agent dithionite on ATPase activity in mitochondria from control animals did not take place in fresh mitochondria from treated animals; however, dithionite was effective in these latter mitochondria when tested 5 h later after keeping them at 10 degrees C. The intravenous infusion of oleic acid produced a rise in the [NADH]/[NAD+] and [Total flavin]/[FAD] ratios in mitochondria, and values double as those in the controls were observed; these values gradually approached those of the control mitochondria when kept at 10 degrees C; after 24 h these ratios were the same in mitochondrial suspensions from treated and nontreated animals. These results suggest that the modification of the properties of mitochondrial ATPase induced by glucagon or fatty acids might be mediated by a change in the mitochondrial redox state.


New approaches to antiretroviral drug delivery: challenges and opportunities associated with the use of long-acting injectable agents.
Research on improved treatment of HIV infection and pre-exposure prophylaxis continues. Poor adherence to treatment is the critical risk factor for virological failure and resistance development, and long-acting formulations of anti-HIV medications that need only infrequent dosing may facilitate long-term therapeutic responses. Importantly, long-acting formulations of therapeutic agents have been used to avoid missing doses or treatment fatigue to prescribed lifelong medications in a number of different medical fields, with demonstrable success. However, such formulations are associated with challenges, such as the prolongation of adverse events with the persistence of drug concentrations and concerns over the development of resistance as a result of selective pressure as drug concentrations decline. Furthermore, long-acting injectable formulations of antiretroviral (ARV) agents with infrequent dosing may be advantageous over daily oral drug intake to prevent transmission of HIV. However, the knowledge on protective drug concentrations and frequency of dosing is poor to date and implementation globally is challenging. Importantly, if nanoformulations of ARVs requiring lower drug doses become available globally, the potential for treatment cost reductions is high, as, especially in resource-limited settings, the active pharmaceutical ingredient accounts for the greater proportion of the total cost of the medicine. In conclusion, different long-acting ARVs are being studied in phase I/II for both the treatment and prevention of HIV infection, and research on administering these agents in combination has started.


Sexually dimorphic functional alterations of rat hepatic glucocorticoid receptor in response to fluoxetine.
Gender-related differences in the expression and functional properties of the hepatic glucocorticoid receptor were studied before and after antidepressant fluoxetine administration to both unstressed and rats exposed to a chronic social isolation stress. Some of the receptor's functional properties, including hormone-binding capacity (B(max)), hormone-binding potency (B(max)/K(D) ratio) and the DNA-binding ability, were found to be sexually dimorphic. Fluoxetine treatment (5mg/kg body mass, 21day, intraperitoneally) induced a decrease in B(max) and in the amount of Hsp70 co-immunoprecipitated with the glucocorticoid receptor only in males, and stimulated the association of the receptor with Hsp90 in females. When applied during the last three weeks of the 6-week isolation, fluoxetine parallelly elevated B(max) and the receptor protein level in female animals, while in males diminished B(max) and inhibited association of the receptor with Hsp70. Binding of dexamethasone-receptor complexes both to DNA-cellulose and to isolated liver nuclei did not appear to be a target for fluoxetine action. The results point to sex-related differences in the glucocorticoid receptor functioning and in its response to fluoxetine, and suggest that these differences may contribute to well known sexual dimorphism in the sensitivity to stress, to stress-related disorders and to antidepressant treatment.


The large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase is fragmented into 37-kDa and 16-kDa polypeptides by active oxygen in the lysates of chloroplasts from primary leaves of wheat.
Lysates of chloroplasts isolated from wheat (Triticum aestivum L. cv. Aoba) leaves were incubated on ice (pH 5.7) for 0 to 60 min in light (15 mumol quanta m-2 s-1), and degradation of the large subunit (LSU) of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco: EC 188.8.131.52) was analyzed by applying immunoblotting with site-specific antibodies against the N-terminal, internal, and C-terminal amino acid sequences of the LSU of wheat Rubisco. The most dominant product of the breakdown of the LSU and that which was first to appear was an apparent molecular mass of 37-kDa fragment containing the N-terminal region of the LSU. A 16-kDa fragment containing the C-terminal region of the LSU was concomitantly seen. This fragmentation of the LSU was inhibited in the presence of EDTA or 1,10-phenanthroline. The addition of active oxygen scavengers, catalase (for H2O2) and n-propyl gallate (for hydroxyl radical) to the lysates also inhibited the fragmentation. When the purified Rubisco from wheat leaves was exposed to a hydroxyl radical-generating system comprising H2O2, FeSO4 and ascorbic acid, the LSU was degraded in the same manner as observed in the chloroplast lysates. The results suggest that the large subunit of Rubisco was directly degraded to the 37-kDa fragment containing the N-terminal region and the 16-kDa fragment containing the C-terminal region of the LSU by active oxygen, probably the hydroxyl radical, generated in the lysates of chloroplasts.


The effect of Arvin on reticuloendothelial activity in rabbits.
1. Arvin stimulated the reticulo-endothelial uptake of colloidal carbon in rabbits. The onset of effect after intravenous administration was immediate and the minimum stimulant dose by this route was very low-0.05 unit/kg (0.1 mug protein/kg).2. Carbon opsonized in vitro with serum taken 4 h after an intravenous injection of Arvin was cleared more rapidly than carbon treated with control serum. Serum collected 10 min after Arvin did not promote carbon uptake.3. Reticulo-endothelial block with Thorotrast or excess carbon did not prevent the stimulant effect of Arvin but prevented the stimulant effect of opsonization with 4 h serum.4. The reticulo-endothelial stimulant effect of Arvin appears to be unrelated to its coagulant action on fibrinogen. The mechanism may involve a direct action on phagocytic cells and an effect on colloidal particles via serum opsonins.


GLUT1 enhances mTOR activity independently of TSC2 and AMPK.
Enhanced GLUT1 expression in mesangial cells plays an important role in the development of diabetic nephropathy by stimulating signaling through several pathways resulting in increased glomerular matrix accumulation. Similarly, enhanced mammalian target of rapamycin (mTOR) activation has been implicated in mesangial matrix expansion and glomerular hypertrophy in diabetes. We sought to examine whether enhanced GLUT1 expression increased mTOR activity and, if so, to identify the mechanism. We found that levels of GLUT1 expression and mTOR activation, as evidenced by S6 kinase (S6K) and 4E-BP-1 phosphorylation, changed in tandem in cell lines exposed to elevated levels of extracellular glucose. We then showed that increased GLUT1 expression enhanced S6K phosphorylation by 1.7- to 2.9-fold in cultured mesangial cells and in glomeruli from GLUT1 transgenic mice. Treatment with the mTOR inhibitor, rapamycin, eliminated the GLUT1 effect on S6K phosphorylation. In cells lacking functional tuberous sclerosis complex (TSC) 2, GLUT1 effects on mTOR activity persisted, indicating that GLUT1 effects were not mediated by TSC. Similarly, AMP kinase activity was not altered by enhanced GLUT1 expression. Conversely, enhanced GLUT1 expression led to a 2.4-fold increase in binding of mTOR to its activator, Rheb, and a commensurate 2.1-fold decrease in binding of Rheb to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) consistent with mediation of GLUT1 effects by a metabolic effect on GAPDH. Thus, GLUT1 expression appears to augment mesangial cell growth and matrix protein accumulation via effects on glycolysis and decreased GAPDH interaction with Rheb.


Ventral and Dorsal Stream EEG Channels: Key Features for EEG-Based Object Recognition and Identification.
Object recognition and object identification are multifaceted cognitive operations that require various brain regions to synthesize and process information. Prior research has evidenced the activity of both visual and temporal cortices during these tasks. Notwithstanding their similarities, object recognition and identification are recognized as separate brain functions. Drawing from the two-stream hypothesis, our investigation aims to understand whether the channels within the ventral and dorsal streams contain pertinent information for effective model learning regarding object recognition and identification tasks. By utilizing the data we collected during the object recognition and identification experiment, we scrutinized EEGNet models, trained using channels that replicate the two-stream hypothesis pathways, against a model trained using all available channels. The outcomes reveal that the model trained solely using the temporal region delivered a high accuracy level in classifying four distinct object categories. Specifically, the object recognition and object identification models achieved an accuracy of 89% and 85%, respectively. By incorporating the channels that mimic the ventral stream, the model's accuracy was further improved, with the object recognition model and object identification model achieving an accuracy of 95% and 94%, respectively. Furthermore, the Grad-CAM result of the trained models revealed a significant contribution from the ventral and dorsal stream channels toward the training of the EEGNet model. The aim of our study is to pinpoint the optimal channel configuration that provides a swift and accurate brain-computer interface system for object recognition and identification.